1. Technical Field
This document relates to methods and materials involved in assessing responsiveness to poly(ADP-ribose) polymerase (PARP) inhibitors and platinating agents. For example, this document relates to methods and materials for using levels of non-homologous end-joining (NHEJ) pathway members (e.g., artemis mRNA or polypeptide levels) to determine if cancer cells that are homologous recombination (HR)-deficient are likely to be susceptible or resistant to PARP inhibitors and platinating agents.
2. Background Information
PARP1 is an abundant nuclear enzyme that synthesizes ADP-ribose polymer (pADPr) when activated by DNA nicks or breaks. Activation of PARP1 has important effects on a variety of cellular processes, including base excision repair (BER), transcription, and cellular bioenergetics. The role of PARP1 in the DNA damage response sparked interest in the development of PARP inhibitors as potential chemosensitizers for the treatment of cancer. The more recent observation that PARP inhibition is particularly lethal to cells deficient in HR proteins generated additional excitement in the cancer chemotherapy community. The current explanation for this hypersensitivity focuses on a mechanism in which loss of PARP1 activity is thought to result in accumulation of DNA single-strand breaks (SSBs), which are subsequently converted to DNA double strand breaks (DSBs) by the cellular replication and/or transcription machinery. These DSBs, which are repaired by HR in BRCA-positive cells, are presumed to accumulate in BRCA1- or BRCA2-deficient cells, leading to subsequent cell death. Heightened sensitivity to PARP inhibition has also been observed in cells with other genetic lesions that affect HR, including phosphatase and tensin homolog (PTEN) deficiency (Mendes-Pereira et al., EMBO Mol. Med., 1:315-322 (2009)), ataxia telangiectasia mutated (ATM) deficiency (Williamson et al., Mol. Canc. Ther., 9:347-357 (2010) and Weston et al., Blood, 116:4578-4587 (2010)), and Aurora A overexpression (Sourisseau et al., EMBO Mol. Med., 2:130-142 (2010)).